Dosis Dan Respon Obat

HUBUNGAN DOSIS, KONSENTRASI DENGAN RESPON OBAT

Oleh : Neni Anggraeni (130120150011

Mata Kuliah : FarmakodinamikDosen Pengampu : Kuswinarti, Dra., MS,

Apt

Obat dapat memberikan respon ketika berikatan dengan suatu reseptor

Dosis Manfaat maksimum & Toksisitas minimum

Dosis & Respon pada PasienVariasi dalam respon obatSelektivitas klinik

Dosis & Respon pada Pasien

Graded Dose-Respon RelationUntuk Menentukan dosis obat yang tepat, harus diketahui mengenai The relative pharmacologic potency and maximal efficacy

1. PotencyDrugs A and B more potent than drugs C and D

Potensi bergantung pada :• Kemampuan obat tersebut

mencapai reseptor yang sesuai• Cara pemberian• Absorbsi • Distribusi• Klirens dari darah atau tempat

kerjanya

Potensi suatu obat harus dinyatakan dalam unit dosis. 50 mg untk sedasi ringan, 1µg/kg/men untuk peningkatan denyut jantung

2. Maximal EfficayThis parameter reflects the limit of the dose-response relation on the response axis.Drugs A, C, and D have equal maximal efficacy, and all have greater maximal efficacy than drug B.

Efekasi ditentukan oleh interaksi obat dengan reseptor atau oleh reseptor-efektor yang terlibat

Dosis & Respon pada Pasien

Shape of Dose-Response CurvesRespon yang terlihat dalam kurva A,B,C mendekati hubungan Michaelis-Menten

Kurva yang curam (D) mempunyai konsekuensi klinik yang penting. (koma hipnotik-sedativ)

Kurva yang curam diakibatkan interaksi kooperatif dari beberapa kerja suatu obat yang berbeda.

Sifat Farmakokinetik suatu obat

Dosis & Respon pada Pasien

Quantal Dose-Effect CurvesGraded dose-response curves of the sort described above have certain limitations in their application to clinical decision making

if the pharmacologic response is an either-or (quantal) event, such as prevention of convulsions, arrhythmia, or death

Dosis & Respon pada Pasien

Determining the dose of drug required to produce a specified magnitude of effect in a large number of individual patients or experimental animals and plotting the cumulative frequency distribution of responders versus the log dose.

Quantal Dose-Effect Curves

Dosis & Respon pada Pasien

Quantal Dose-Effect CurvesMedian effective dose (ED50) = is the dose at which 50% of individuals exhibit the specified quantal effect.

Median toxic dose (TD50) = the dose required to produce a particular toxic effect in 50% of animals

If the toxic effect is death of the animal = median lethal dose (LD50)

Dosis & Respon pada Pasien

Quantal Dose-Effect Curves

Jika ada dua obat A dan B menghasilkan ED50, A = 5mg dan B = 500 mg. Maka obat A 100 kali lebih kuat untuk menghasilkan efek kuantal tertentu

Dosis & Respon pada Pasien

Quantal Dose-Effect Curves

Dapat memberikan informasi mengenai batas keamanan suatu obat.

Indeks terapi = ukuran yang menghubunkan dosis obat untuk menghasilkan efek yang diingingkan terhadap efek yang tidak diinginkan

Indeks terapi = rasio TD50 terhadap ED50.

Dosis & Respon pada Pasien

Quantal Dose-Effect Curves Vs Shape of Dose-Response Curves

Both curves provide information regarding the potency and selectivity of drugs; the graded dose-response curve indicates the maximal efficacy of a drug, and the quantal doseeffect curve indicates the potential variability of responsiveness among individuals.

Variasi dalam Respon Obat

Individuals may vary considerably in their response to a drug

Idiosyncratic drug response. Genetik atau mekanisme imunologi (alergi)

• hyporeactive • hyperreactive

4 general mechanisms may contribute to variation in drug responsiveness :

•Alteration in Concentration of Drug That Reaches the Receptor•Variation in Concentration of an Endogenous Receptor Ligand•Alterations in Number or Function of Receptors•Changes in Components of Response Distal to the Receptor

Alteration in Concentration of Drug That Reaches the Receptor

Variasi dalam Respon Obat

patients may differ in :•the rate of absorption of a drug •distributing it through body compartments•clearing the drug from the blood

Some differences can be predicted on :•Age•Weight•Sex•Disease state•Liver and kidneyGenetic differences

Variation in Concentration of an Endogenous Receptor Ligand

Variasi dalam Respon Obat

This mechanism contributes greatly to variability in responses to pharmacologic antagonists

propranolol, a β-adrenoceptor antagonist, markedly slows the heart rate of a patient whose endogenous catecholamines are elevated (as in pheochromocytoma) but does not affect the resting heart rate of a well-trained marathon runner.

Alterations in Number or Function of Receptors

Variasi dalam Respon Obat

In some cases, the change in receptor number is caused by other hormones; for example, thyroid hormones increase both the number of β-andrenoreceptors in rat heart muscle and cardiac sensitivity to catecholamines.

In other cases, the agonist ligand itself induces a decrease in the number (eg, down-regulation) or coupling efficiency (eg,desensitization) of its receptors.

Genetic factors also can play an important role in altering the number or function of specific receptors. For example, a specific genetic variant of the α2C adrenoceptor when inherited together with a specific variant of the α1 adrenoceptor—confers increased risk for developing heart failure, which may be reduced by early intervention using antagonist drugs.

Changes in Components of Response Distal to the Receptor

Variasi dalam Respon Obat

Although a drug initiates its actions by binding to receptors, the response observed in a patient depends on the functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ system

Selektivitas Klinik

no drug causes only a single, specific effect.

In drug development and in clinical medicine, selectivity is usually considered by separating effects into two categories: beneficial or therapeutic effects versus toxic or adverse effects

Selektivitas Klinik

Beneficial and Toxic Effects Mediated by the Same Receptor-Effector Mechanism

Much of the serious drug toxicity in clinical practice represents a direct pharmacologic extension of the therapeutic actions of the drug

a drug is clearly necessary and beneficial but produces unacceptable toxicity when given in doses that produce optimal benefit.

Contoh : Guenetidin. Menurunkan tekanan darah pada hipertensi esensial dgn menghambat stimulasi kardiovaskuler oleh safa simpatis. Jika dosis cukup besar pasien akan mengalamai hipotensi postural.

Selektivitas Klinik

Beneficial and Toxic Effects Mediated by Identical Receptors but in Different Tissues or by Different Effector Pathway

Many drugs produce both their desired effects and adverse effects by acting on single receptor type in different tissues. Ex. Digitalis glycosides, which act by inhibiting Na+/K+-ATPase in cell membranes; methotrexate, which inhibits the enzyme dihydrofolate reductase; and glucocorticoid hormones.

Three therapeutic strategies are used to avoid or mitigate this sort of toxicity. 1.the drug should always be administered at the lowest dose that produces acceptable benefit.2.Adjunctive drugs that act through different receptor mechanisms and producedifferent toxicities may allow lowering the dose of the first drug, thus limiting its toxicity.3.Selectivity of the drug’s actions may be increased by manipulating theconcentrations of drug available to receptors in different parts of the body

Selektivitas Klinik

Beneficial and Toxic Effects Mediated by Different Types of Receptors

Therapeutic advantages resulting from new chemical entities with improved receptor selectivity were mentioned earlier in this chapter and are described in detail in later chapters. Such drugs include α- and β-selective adrenoceptor agonists and antagonists, H1 and H2 antihistamines, nicotinic and muscarinic blocking agents, and receptor-selective steroid hormones